PROJECT SUMMARY/ABSTRACT The Genomic Instability, Epigenetics and Metabolism (GEM) Research Program represents a restructuring and programmatic expansion of the former Redox Injury and Repair (RR) Research Program to reflect burgeoning research strengths of participating members with expertise in highly complementary research thrusts. GEM research efforts are central to the overall Markey Cancer Center (MCC) mission to decrease the burden of cancer in Kentucky, surrounding communities and the nation. GEM investigators determine genetic, epigenetic and metabolic mechanisms that promote cancer development, fuel tumor progression and contribute to therapeutic resistance. The overall goal of this program is to gain a comprehensive understanding of the basic mechanisms of these processes to facilitate development of novel and rational approaches for cancer prevention and therapy. To achieve this goal, GEM has established 3 inter-related themes: 1) research into genomic instability and DNA repair will identify how innate DNA repair pathways interact with environmental mutagens to impact carcinogenesis; 2) research on epigenetic mechanisms of malignancy will delineate how alterations in the epigenome and gene transcription influence carcinogenesis; and 3) research on cancer metabolic reprogramming will decipher the role of metabolic processes that contribute to cancer development with a focus on mitochondrial function and redox-mediated dysregulations. The themes are conceptually linked and feature robust faculty collaboration. GEM program members are pioneers and experts in redox biology, DNA repair, epigenetic regulation and cancer metabolism. The program consists of 18 members from 6 departments in the Colleges of Medicine and Arts and Sciences. The program's cancer- related funding is over $4.9M total annual funding ($3.3M direct costs, of which 33% is from the National Cancer Institute). GEM program members have actively used MCC Shared Resource Facilities since initial Cancer Center Support Grant funding in 2013. Members have published 164 manuscripts (2013 to 2017), of which 72 (44%) are inter-programmatic, 36 (22%) are intra-programmatic, and 99 (60%) are inter-institutional. The program is co-led by 2 researchers with complementary scientific and leadership expertise. Dr. John D'Orazio (a physician scientist focusing on DNA repair) and Dr. Peter Zhou (a specialist in epigenetic and metabolic reprogramming of epithelial-mesenchymal transmission) bring together expertise in genetic instability and cancer (D'Orazio, Theme 1), epigenetic regulation, and metabolism (Zhou, Themes 2 and 3). In addition to their scientific leadership roles, each offers significant strengths in clinical translation, junior faculty mentoring, communications among MCC programs, and expertise on populations within the MCC catchment area.